Enfortumab vedotin showed strong clinical activity in patients with locally advanced or metastatic urothelial carcinoma who previously received both platinum-containing chemotherapy and immune checkpoint therapy, according to topline results from the pivotal phase II EV-201 trial.
Enfortumab vedotin showed strong clinical activity in patients with locally advanced or metastatic urothelial carcinoma who previously received both platinum-containing chemotherapy and immune checkpoint therapy, according to topline results from the pivotal phase II EV-201 trial announced by Seattle Genetics and Astellas, the manufacturers of the antibody-drug conjugate (ADC).
In the single-arm EV-201 trial, enfortumab vedotin induced a 44% objective response rate (ORR) per independent review.1 The duration of response was comparable to findings from the phase I EV-101 trial, which supported the FDA breakthrough therapy designation the ADC received in March 2018 for the treatment of patients with locally advanced or metastatic urothelial cancer who progressed after receiving a PD-1 or PD-L1 inhibitor.
Seattle Genetics and Astellas plan to present further findings from the trial at an upcoming medical conference. Based on the EV-201 data, the companies also intend to submit a biologics license application to the FDA by the end of this year.
“Despite recent approvals of multiple checkpoint inhibitors for previously treated locally advanced or metastatic urothelial cancer, there remains a high unmet need for effective treatments upon progression after initial chemotherapy and immunotherapy,” Roger Dansey, MD, chief medical officer at Seattle Genetics, said in a statement. “These results for enfortumab vedotin indicate it may be able to help patients whose urothelial cancer progresses following treatment with standard chemotherapy and a PD-1 or PD-L1 inhibitor.”
Enfortumab vedotin consists of an anti—Nectin-4 monoclonal antibody attached to the microtubule-disrupting agent MMAE using proprietary linker technology from Seattle Genetics. In the ongoing EV-201 trial, the ADC is being explored in patients with advanced or metastatic urothelial carcinoma in 2 cohorts. Cohort 1 (n = 128) comprises patients treated with an anti–PD-1/PD-L1 agent and platinum-containing chemotherapy, and cohort 2 comprises patients who received a PD-1/PD-L1 inhibitor but were not treated with platinum-based chemotherapy and are not eligible for cisplatin.
ORR is the primary endpoint, with secondary outcome measures including duration of response, disease control rate, progression-free survival, overall survival, safety, and tolerability. The results announced today were for patients from cohort 1. The most frequently reported treatment-related adverse events among patients in cohort 1 were fatigue, alopecia, decreased appetite, rash, and peripheral neuropathy.
Results from the earlier phase I EV-101 trial were presented at the 2017 ASCO Annual Meeting. At the data cutoff of April 28, 2017, 81 patients had received enfortumab vedotin at study sites in the United States in Canada, including 21 in dose-escalation cohorts and 60 in dose-expansion cohorts.
The median patient age was 67 years (range, 41-84), 70% of patients were male. Ninety-five percent of patients had prior platinum-based therapy, 46% had received a checkpoint inhibitor, and 43% had prior taxable treatment. Ninety-seven percent of patients showed nectin-4 expression.
Among 71 evaluable patients across the entire cohort, the ORR was 41% (95% CI, 29.3-53.2), including 3 (4%) complete responses (CRs) and 26 (37%) partial responses (PRs).
Among 30 evaluable patients treated at the RP2D, the ORR was 53% (95% CI, 34.3-71.7), including 1 (3%) CR and 15 (50%) PRs. Six patients had stable disease and 6 had progressive disease. Among patients who had previously received a checkpoint inhibitor who were treated at the RP2D (n = 17), the ORR was 47% (n = 8), consisting of all PRs. Five patients had stable disease.
Twenty-one (26%) patients were still receiving treatment at the cutoff, with 60 (74%) having discontinued. The median time on treatment was 15.1 weeks (range, 1.1-64.6). The reasons for treatment discontinuation included radiographic disease progression (46%), disease progression shown through clinical symptoms (6%), adverse events (AEs; 12%), withdrawal of subject consent (5%), investigator decision (4%), and other (1%).
Among 38 patients receiving the RP2D, the most common all-grade AEs were nausea (37%), pruritus (32%), fatigue (32%), diarrhea (32%), alopecia (32%), decreased appetite (29%), and dysgeusia (21%).
Grade ≥3 AEs in the RP2D cohort included urinary tract infection (8%), hypophosphatemia (3%), hyponatremia (5%), anemia (8%), and hyperuricemia (5%). Across all treatment doses, there were 3 patient deaths (cardiac arrest, small intestinal perforation and sepsis, and acute renal failure), none of which was considered to be related to enfortumab vedotin.